Chemotherapy has improved survival rates in patients with many of the common cancers. However, one of the most common complications of chemotherapeutic drugs is toxicity to the central nervous system (CNS), named chemotherapy-induced cognitive impairment, chemotherapy-induced cognitive dysfunction, post-chemotherapy cognitive impairment (PCCI), chemo fog, or chemo brain. Chemo brain can be very frustrating both for those who are living with cancer, and their loved ones who are trying to support them. Chemo brain can seriously affect quality of life and life itself in cancer patients. This toxicity can manifest in many ways, including encephalopathy syndromes and confusional states, seizure activity, headache, cerebrovascular complications and stroke, visual loss, cerebellar dysfunction, and spinal cord damage with myelopathy. There is reliable evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for many years after the completion of chemotherapy. These include attention deficits, memory loss, and confused thought processes. Up to 70% of patients report that their cognitive difficulties persist well beyond the duration of treatment. Studies that have measured cognitive function using standardized neuropsychological assessments have found mild to moderate effects of chemotherapy on cognitive performance in 15-50% of the survivors after treatment. Longitudinal studies have shown that, in a subset of survivors, cognitive difficulties can persist for between 1 and 2 years after the completion of chemotherapy. Cross-sectional studies have found cognitive impairments lasting between 4 and 10 years after chemotherapy. Although recent prospective studies show that about 20% of cancer patients experience cognitive dysfunction even before chemotherapy, chemotherapy agents produce significant cognitive impairment in laboratory animals that are free from cancer as well as from other treatment- and diagnosis-related factors. Healthy rodents that are given chemotherapy show increase in cell death in the central nervous system, increase in oxidative stress, increase in microglia activity, suppression of hippocampal neurogenesis, decreases in levels of neurotrophic factors, and decreases in levels of hippocampal catecholamines, as compared to baseline values. The etiology of chemotherapy-induced cognitive impairment is largely unknown, but several candidate mechanisms have been suggested, including oxidative stress, impaired blood-brain barrier (BBB), neuroinflammation, decreased neurogenesis, etc.
Oxidative stress plays a key role in cognitive disorders caused by certain type of anticancer drugs, such as antimetabolites, mitotic inhibitors, topoisomerase inhibitors and paclitaxel etc. These chemotherapeutic agents are not known to rely on oxidative mechanisms for their anticancer effects. Among the antimetabolite drugs, methotrexate (MTX), 5-fluorouracil (5-FU, a widely used chemotherapeutic agent), and cytosine arabinoside are most likely to cause CNS toxicity. 5-FU can cause both acute and delayed neurotoxicity. Acute neurotoxicity manifests as encephalopathy cerebellar syndrome or as seizures. Acute neurotoxicity due to 5-FU is dose-related and generally self-limiting. 5-FU readily crosses the blood-brain barrier and disrupts cell proliferation. Clinically relevant concentrations of 5-FU were toxic for both central nervous system (CNS) progenitor cells and non-dividing oligodendrocytes in vitro and in vivo. Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment. Delayed neurotoxicity has been reported when fluorouracil was given in combination with levamisole; this form of subacute multifocal leukoencephalopathy is immune mediated. Although no report for 5-FU to increase CNS oxidative stress has been found yet, it has been indicated inducing apoptosis in rat cardiocytes through intracellular oxidative stress, increasing oxidative stress in the plasma of liver cancer patients, and decreasing glutathione in bone marrow cells. Another antimetabolite MTX can cross the blood-brain barrier as well. It resulted in an increase of oxidative stress in cerebral spinal fluid and executive dysfunction in MTX-treated patients of pediatric acute lymphoblastic leukemia. A recent observation also indicates that genetic polymorphism for methionine is a potent risk factor for MTX-induced central nervous system toxicity.
Oxidative stress could be a common path for chemotherapy-induced cognitive impairment and neurodegenerative diseases. Oxidative stress can cause single and double DNA strand breaks and is the most frequent cause of DNA damage in neuronal cells. Oxidative damage can occur through exposure to foreign agents or result from an endogenous mechanism. Oxidative damage has been associated with numerous neurodegenerative diseases such as Alzheimer's disease and Parkinson's. Patients displaying mild cognitive impairment exhibit higher levels of oxidative DNA damage in both peripheral leukocytes and the brain. Many chemotherapeutic agents take advantage of the DNA damaging effects of oxidative stress; however, the effects of oxidative stress are not confined to abnormal cells. Evidence of oxidative damage has been seen in peripheral blood lymphocytes in breast cancer patients treated with chemotherapy. In addition, chemotherapy patients displayed decreased DNA repair abilities. Chemotherapy treatment is associated with increased levels of nonprotein bound iron, increased levels of free radicals, and decreased antioxidant capacity, all factors suggested to increase oxidative stress. It is proposed that MTX treatment inhibits protective factors that may prevent radical damage. As a result, poly-unsaturated fatty acid chains within the cell membranes are more susceptible to attack by reactive oxygen species. These initial attacks signal other lipid peroxy radicals to form, triggering a cascade of cell membrane damage.
Currently there are no proven treatments for chemotherapy-induced cognitive impairment. Some efforts have been focused on correcting cognitive deficits rather blocking neurotoxic pathway that was induced with chemotherapeutical drug. These include erythropoietin (a glycoprotein to stimulate the production of red blood cells), methylphenidate (modulating catecholaminergic tone), modafinil (releasing catecholamines, norepinephrine, dopamine and histamine), donepezil (a cholinesterase inhibitor), and fluoxetine (a selective serotonin reuptake inhibitor). In contrast to above, antioxidative treatment would be a promising strategy for the treatment. Consumption of foods high in antioxidants and antioxidant supplementation appear to slow the rate of cognitive decline associated with aging and disease in humans and rodents. Several preclinical studies have shown that antioxidant treatment prevents chemotherapy-induced oxidative stress and cognitive deficits when administered prior to and during chemotherapy. For example, systemic treatment in healthy mice with γ-glutamyl cysteine ethyl ester prior to doxorubicin treatment significantly decreased markers of oxidative stress, namely, protein oxidization and lipid peroxidization. However, behavior was not assessed in this study. Prior intracerebroventricular treatment with the antioxidant zinc sulfate (ZnSO4) prevented short-term memory impairments induced by systemic carmustine (BCNU) treatment. Specifically, BCNU treatment caused rats to make more errors during learning and recall of the radial arm maze, whereas treatment with ZnSO4 prior to BCNU prevented these deficits in learning and memory. In addition, hippocampal cell death and inflammation induced by BCNU treatment were prevented in rats pretreated with ZnSO4. Another case for reduction of anticancer drug-caused cognitive deficit with antioxidant is that there was no short-term memory impairment when rats that received cyclophosphamide and doxorubicin were treated with the antioxidant N-acetyl cysteine during chemotherapy. A recent review of 29 placebo-controlled randomized control trials of cancer survivors with deficits confirmed, by comparing psychometric tests, that the greatest benefits of Ginkgo biloba were found in executive functioning, selective attention, and memory.
Taken together, this information suggests that treatment with antioxidants prior to and during chemotherapy prevents the occurrence of cognitive deficits shortly after chemotherapy. Human trials of antioxidant supplementation in patients with breast and lung cancer have demonstrated an increase in survival, although alkylating agents, antitumor antibiotics, and topisomerase II inhibitors depend on the generation of free radicals for their therapeutic action. It was found, by investigating the MEDLINE® and CANCERLIT® databases from 1965 to November 2003, that antioxidants and other nutrients do not interfere with chemotherapy of alkylating agents (e.g. cisplatin), antitumor antibiotics (e.g. doxorubicin) and topoisomerase II inhibitor (e.g. etoposide) or radiation therapy and can increase kill and increase survival.
As there are no proven treatments, there is a need for methods to properly treat chemotherapy-induced cognitive impairment. The present invention provides just such a method.